17alpha-(2-alkynyl)-11beta-methylestra-1 3 5(10)-triene-3 17beta-diols and esters thereof

ABSTRACT

17A - (2 - ALKYNYL) - 11B - METHYLESTRA - 1,3,5(10)TRIENE - 3,17B - DIOLS AND ESTERS THEREOF EXHIBIT USEFUL PHARMACOLOGICAL PROPERTIES, E.G. DECIDUOGENIC, AND ARE MANUFACTURED BY REACTION OF THE CORRESPONDING 17-KETO STARTING MATERIALS WITH THE APPROPRIATE 2-ALKYNYL ORGANOMETALLIC REAGENT OPTIONALLY FOLLOWED BY ACYLATION OF THE RESULTING HYDROXY COMPOUNDS.

United States Patent 3,658,853 17a-(2-ALKYNYL)-11/3-METHYLES'I'RA-1,3,5(10)- TRIENE-3,17B-DIOLS AND ESTERS THEREOF Paul D. Klimstra, Northbrook, lll., assignor to G. D. Searle & Co., Chicago, Ill.

No Drawing. Filed Mar. 5, 1970, Ser. No. 16,928 Int. Cl. C07c 169/08 U.S. Cl. 260-3975 6 Claims The present invention is concerned with novel acetylenic steroidal alcohols and esters and, more particularly, with 170: (2 alkynyl) 115 methylestra 1,3,5(l0)- triene-3,17B-diols and esters thereof represented by the following structural formula wherein R and R can be either hydrogen or a lower alkanoyl radical.

The lower alkyl radicals encompassed by the foregoing structural representation are typified by methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and the branchedchain isomers thereof.

Examples of the lower alkanoyl radicals within the scope of the formula are formyl, acetyl, propionyl, butyryl, valeryl, caproyl, heptanoyl and the corresponding branched-chain isomeric groups.

The novel compounds of this invention are conveniently manufactured by utilizing 3 hydroxy llfi-methylestra 1,3,5 trien 17 one as the starting material. That substance is converted to the 3 tetrahydropyran- 2'-yl ether, suitably by reaction with dihydropyran in the presence of p-toluenesulfonic acid, and that ether is allowed to react with a 2-alkynyl organometallic reagent. The reaction of 11/8 methyl 3 tetrahydropyran-2'- yloxy estra 1,3,5 (10)-trien-17-one with the Grignard reagent prepared from 1 bromo 2 butyne and magnesium thus aifords 17c: (2 butynyl) 11B methylestra 1,3,5(10) triene 3,1713 diol 3-tetrahydropyran 2'-yl ether. Cleavage of the ether protecting group to afford the free diol, i.e. 17a (2 butynyl) 11B methylestra 1,3,5(10) triene 3,1713 diol, is readily effected by reaction with an acidic reagent such as p-toluenesulfonic acid.

The instant esters are obtained by acylation of the corresponding hydroxy compounds. When the aforementioned diols are contacted with a lower alkanoic acid anhydride or halide, preferably in the presence of a suitable acid acceptor such as pyridine or triethylamine, selective acylation of the 3-hydroxy group occurs when the process is conducted at room temperature. The reaction of 17a (2 butynyl) 11B methylestra 1,3,5(10)- triene-3,17B-diol with acetic anhydride and pyridine at room temperature thus affords the corresponding 3-acetate. At elevated temperature acylation of the 17-hydroxy Patented Apr. 25, 1972 group occurs also, in the latter example thus resulting in the corresponding 3,17-diacetate. V

The compounds of this invention display valuable pharmacological properties. They are, for example, hormonal agents as is evidenced by their deciduogenic properties.

In addition, they lack the potent side-effects, e.g., estrogenic, possessed by related prior art compositions.

The deciduogenic property of the instant compounds is specifically illustrated by the activity of 17a (2 butynyl) 1118 methylestra 1,3,5(l0) triene 3,173 diol and 17a (2 butynyl) 11/3 methylestra 1,3,5(l0)- triene-3,17B-diol 3-acetate when tested in the following assay procedure:

Intact immature female rats weighing about 1 kg. are primed with 5 mcg. subcutaneous injections of estradiol- 175 on each of 6 successive days. Starting on the day following the last priming injection and continuing on each of eight successive days thereafter, a corn oil solution or suspension of the selected dose of the test compound is administered subcutaneously. On the ninth day, the animals are sacrificed and the uteri are removed and examined histologically for evidence of decidual cell formation. A compound is considered active if it causes the appearance of decidual cells in the uterus.

The invention will appear more fully from the examples which follow. These examples are meant by way of illustration only and are not to be construed as limiting the invention either in spirit or in scope as many modifications both in materials and in methods will be apparent to those skilled in the art. In these examples, temperatures are given in degrees centigrade C.) and quantities of materials in parts by weight unless otherwise noted.

EXAMPLE 1 A mixture containing 3.66 parts of 3-hydroxy-l1 3- methylestra-1,3,5(10)-trien-17-one, 2.7 parts of dihydropyran, 0.01 part of p-toluenesulfonic acid monohydrate and 53 parts of benzene is allowed to stand at room temperature for about 16 hours, then is filtered to remove a small amount of insoluble material. To that mixture is then added 02 part of pyridine and the solvent is removed by distillation under reduced pressure to afford an oily residue. That oil solidifies upon standing, thus yielding 3- tetrahydropyran 2' yloxy 11B-methylestra-l,3,5(10)- trien-17-one, which compound exhibits infrared absorption maxima, in chloroform, at about 3.39, 5.74, 6.21, 6.65, 8.10, 9.63 and 10.26 microns.

EXAMPLE 2 A mixture containing 1.2 parts of magnesium turnings, 0.06 part of mercuric chloride and 35 parts of ether is stirred at 0-5 and a solution of 5 parts of 1-bromo-2- butyne in 35 parts of ether is added over a period of about minutes. A small quantity of iodine is added at the beginning of the latter addition in order to initiate the reaction. The mixture is cooled, then stirred for an additional hour following completion of the addition. At the end of that time a solution of 3 parts of 3-tetrahydropyran 2'-yloxy-1 l ,3-methylestra-1,3,5 l0)-trien-l7-one in 45 parts of tetrahydrofuran is added dropwise with cooling over a period of about 1 hour. Stirring at 0-5 is continued for about 1 hour, following which time the mixture is heated at the reflux temperature for about 16 hours. It is then cooled and excess saturated ammonium chloride is added. The mixture is diluted with ether and the organic layer is separated, Washed several times with water, dried over anhydrous sodium sulfate containing decolorizing carbon and stripped of solvent under reduced pressure to afford an oily residue containing 17a-(2-butynyl)-1lflmethyl 3-tetrahydropyran-2-yloxyestra-l,3,5(10)-trien- 17 3-01.

thelatteri-esidueis added 0.1 part of p-toluenesul-M fonic acid monohydrate and 80 parts of methanol and that reaction mixture is kept at room temperature for about 45 minutes. To themixture is then .addeda llipart of pyridine and the solvent is distilled under redubedjp're's sure. The brown oily residueis purifiedbyadsorptionron silica gel "and elution with ethyl acetate in benzene, Thee luted' fraction is purified'fu'rther by recrystallization frJoinfaqueous methanol, thus alfording"17 x(2-hutynyl)5 111B methylestra-l,3, 5-(10)-triene-3,l7;3 diol, "meltiug at about 145-1487. This compound exhibits an optical rotation, in chloroform, of +38 and is further characterized following structural formula j QEXAMPLE 3 I H aqueous mixture is extracted with benzene and the ben- 3 l7-dipropionate.

zene layer is separated, washed with water, dried over anhydrous sodium sulfate containing decolorizing carbon and concentrated under reduced pressure to aflord 170c- (2-butynyl) -l l fi-methylestra- -l ,3,5 l 0) -triene 3,17fi-diol 3,17rdiacetate. I I 1 EXAMPLE 8 By substituting an equivalent quantity of propionic anhydride and otherwise proceeding according to the processes described in Example 7, there is produced 17ot-(2- butynyl); 115 methylestra l,3,5(l0)'-triene-3,l7pdiol XAMP E The substitution of an equivalent quantity of 1 lB-methyl-l7oi-(2-pentynyl)estra 1,3,5('10') triene 3,17B-dio1 in'the procedure of Example 3' affords llfi-methyl-lhmixturecontaining 2.3-parts ofl7a-(2 butynyl)-1-l;3-i

methylestra-l,3',5 (10) triene-3,17B-diol;ISparts of acetic anhydride and 30 parts of pyridine is allowed to stand at room temperatur'e'for about 16 hours,;then is diluted with methanol and water; 'I'heresulting mixtur isco'oled. at (PS until separation of the oily-product is complete. That oil is extracted into ether and the ether solution is washed successively with water, dilute hydrochloric acid, and dilute aqueous sodium bicarbonate, then is dried over anhydrous'sodium sulfate containing decolorizin-g' carbon.

Removal of the solvent by distillation under reduced pres sure affords a glass-like residue. That material is dissolved i'n benzene and is purified by dry chromatography on silica gel. The desired silica gel section is extracted three times with ethyl acetate and the resulting solution is evaporated to dryness under reduced pressure to afford, as an oil, 17a (2 butyny1)-1lfi-methylestra 1,3;5 10)- triene-3,17B-diol 3-acetate. This compound-is represented bythe -followingstructural formula EXAMPLE 4 When an equivalent quantity of propionic anhydride is substituted in the procedure of Examplea3, vthere. is

obtained 17a (2- butynyl)-1 lfl-methylestra-LLS (10)- triene-3,l7p-diol -3-propionate. a

""f'ExAMPLEs I When an equivalent quantity of l-brom Z-pentyne is substituted in the procedure of Example 1; there is pro duced 11p methyl-1 7a-(2-pentynyl)-3-tctrahydropyrau- Z-yloxyestra-1,3,5(1Q)-trien-1,7fi-ol. 1; EXAMPLE/6' I ffwhm an equivalent cjuantity of llfl-niethyl-lju-tzpenty iyl)-3-tetrahydropyran 2 yloxyestra-1,3,5(1 0.)- trien 17fl-o'l is substituted in the procedure fof Example 2, there is produced 1lu-methyl-l7u-(2 pentynyllestra l,

A njixture containing lpart or 17 -(2-liutynyD- 11B. methyle stra-l ,3,5(10 )-trieue 3,175 diol, l'Ofparts of acetic anhydride and 20 parts jof pyridine heated on a steam bath for about 4 hours,"then is cooled and poured carefully into a mixture of ice and water. The resulting What is claimed is:' a 1 compound of the formula I it CH CEC-(IQV-Ier elkyl) wherein R is selected from the group consisting of hydrogen and a lower alkanoyl radical, R"'ishydrogen when R is hydrogen and R is selected from the group consisting or hydrogen an d a lower alkanoyl radical when R is a lower alkan'o'yl radical.

2. As in claim 1, a compound of the formula (lower alkyn c o v V 4. As in claim 1, a compound of the formula Y OH As'inclaim 1, the compound which is 17m (2- hutynyl) -1 lfl-methylestra-lfifi (10)-triene-3,l7j8-diol.

0 in claim 1, the compound which is 17:; (2-

butyriyl) 11B methylestra 1,3,5 (10)-triene-3,l7fi-diol 3-acetatc'z 1 I h a a a a v 1 References Cited T.. ,UNITED,ST,ATES, PATENTS -';2"9'9,'10s {171967 araa 260397.5 3,377,365 fl/1968 1 Baran 260-3915 f "IOVTHXERVREEERENCES 7 hcounsell t al.: I. Med. Chem. 9, 689 (1966).

HEliliYAlERENCI-I, Primary Examiner ULS. cihxn. 260 -23955 R, 999 

